(20s)-3-keto-20-hydroxy-18-oic lactone(?20)-pregna-5-ene and derivatives thereof



Jan. 16, 1968 J. LE MEN 3,364,209

(20S)IB-KETO'ZO-HYDROXY-l8-OIC LACTONE 20) PREGNA-ENE AND DERIVATIVESTHEREOF Filed March 22, 1961 2 Sheets-Sheet l f-vg. 1

Jan. 16, 1968 J. LE MEN 3,364,209

(20S)-5-KETO20HYDROXYlf3-OIC LACVTONE (-ZOFPREGNA-S-ENE AND DERIVATIVESTHEREOF Filed March 22, 1961 2 Sheets-Sheet 2 United States Patent 03,364,209 (20S)3KETO20HYDROXY18OIC LACTONE(- 20) PREGNA-S-ENE ANDDERIVATIVES THEREOF Jean Le Men, Limeil-Brevannes, Seine-et-Oise,France, assignor to Roger Bellon, Charcot, France Filed Mar. 22, 1961,Ser. No. 97,680 Claims priority, application Great Britain, Mar. 25,1960, 10,681/ 60 The portion of the term of the patent subsequent toDec. '15, 1981, has been disclaimed 8 Claims. (Cl. 260-239.57)

This compound as well as the other compounds descri-bed hereinafter aredesignated according to the Rules of Nomenclature established by Cahn,Ingold, and Prelog (Experientia, vol. 12, 1956, page 81).

The applicant has moreover prepared different derivatives ofparavallarine and, starting from this compound, he has obtaineddihydroparavallarine, belonging to the allopregnane series, andconforming to the formula O\ O CH3 /N CH3 as Well as dilferentderivatives of this latter compound. Such derivatives are described inthe above mentioned patent application Ser. No. 61,163 and correspond tothe following formula:

wherein X is a member selected from the group consisting of methyleneand carbonyl;

R1 is a member selected from the group consisting of hydrogen, methyl,and acetyl;

R2 is a member selected from the group consisting of hydroxyl andacetoxy; and

Y and Z are -members selected from the group consisting of hydrogen anda direct carbon to carbon bond.

Such compounds are, for instance, (208)-3-(N-methylamino)-l8,20dihydroxypregna-S-ene and the like compounds.

The present invention provides a process for the preparation ofsteroids, which comprises deaminating paravallarine,dihydroparavallarine, or a derivative of either of these compoundshaving a -NHCH3 grouping in the 3-position.

This deamination can be carried out in accordance with the methoddescribed by H. Ruschig, W. Fritsch, J. Schaidthome and W. Haede (Chem.Ser. 1955, 88, 883).

Accordingly in a first stage, an N-chlorinated derivative ofparavallarine, or a derivative thereof, is prepared and, in a secondstage, the chloramine which has formed is destroyed, for example bymeans of a solution of an alkali metal alcoholate in an anhydrousalcohol to form the 3-keto-group on solvolysis.

In order to effect the first stage, it is possible to useN-chlorosuccinimide or hypochlorous acid as chlorinating agent, thereaction taking place in the cold in an anhydrous organic solvent, suchas an ether or a chlorinated solvent.

The excess of the chlorinating agent is then eliminated, for example bywashing with water and, after having driven off the solvent at atemperature below 40 C., the chloramine which has formed is destroyed inthe second stage.

The deaminated products obtained are novel. They are useful in mineralmetabolism and are intermediates for the synthesis of cortical hormonesas they can be hydroxylated in the 21-position. Furthermore they canserve as intermediates for the preparation of 18-oxygenated steroids,and more particularly steroids comprising a lactone bridge between the18 and 20 positions of steroids of the pregna-4-ene and allopregnanetypes. Furthermore, in accordance with the present invention, ketones ofthe following formula:

QRi

fr H Jl) in which R1 and A have the meanings given above. Furthermore,(20S)-3-keto-20-hydroxy-l8-oic lactone( 20) allopregnane can be reducedto (20S)-3,20dihydroxy 18-oic lactone(20)allopregnane with an alkalimetal borohydride, such as potassium borohydride. The novel(20S)3,20dihydroxy 18 oic lactone(- 20)allopreg nane can be acetylatedwith acetic anhydride to give (205)-3-(-acetoxy)-20-hydroxy 18 oiclactone(- 20) allopregnane.

The following non-limiting examples further illustrate the presentinvention:

EXAMPLE 1 The deamination obtained by the method described below showsthat the double bond originally situated at the 5,6-position migratestowards the 4,5-position to form a conjugated compound with the ketonefunction fixed in the 3-position. This is evident from the appearance ofbands at 6,@ and 6.2# in the infra-red spectrum and the appearance of anabsorption band at 240 ma in the ultraviolet spectrum.

Thus,steroids derived from 3-keto-A4-pregnene are obtained.

A solution of l g. of paravallarine in l5 cc. of methylene chloride ismixed with a solution of 600 mg. of N- chlorosuccinimide in cc. ofmethylene chloride and the mixture is stirred for l5 minutes at atemperature in the region of 0 C. After standing for 45 minutes at anambient temperature, the reaction solution is washed with 50 cc. ofWater four times, it is dried over dry sodium sulphate and distilled ata temperature below 40 C. The white residue is dried for 1 hour at 20C., under a vacuum of 0.01 mm, Hg, and it is treated under reflux for 30minutes With 25 cc. of a solution of sodium ethanolate in ethanol.

A white dense precipitate is observed, this forming as soon as heatingis commenced. The reaction solution, which is yellow in colour, is thenpoured into 150 cc. of a 1% sulphuric acid solution and the precipitateformed is extracted with ether.

There are obtained 305 mg. of a light yellow dry residue. The acidsolution is then heated for 30 minutes at 100 C., on a water bath and asecond precipitate is obtained and extracted with chloroform.

320 mg. of a brownish-yellow residue are produced.

The chromatography of a benzene solution of the first residue provides,by elution with the same solvent, 58 mg. of a white product which isrecrystallised from acetone to form needles; it melts at l98-200 C.; itsrotatory power is []D2=-l92i2 (c.=0.152 chloroform).

The infra-red spectrum of this product is given in the curve shown inFIG. 1 of the accompanying drawings and it is possible to observecharacteristic bands at 5.7M (lactone) 6.0 and 6.2i (unsaturatedketone).

Analysis of the product, for an empirical formula of CarHzaOs, SVCS-Calculated: C=76.79%, H,=8.59%, Found: C='76.59%, H=8.54%, O=14.88%.

Chromatography of the benzenic solution of the second residue (320 mg),as before, supplies by elution with the same solvent 27 mg. of the sameproduct which melts at 198200 C.

4 EXAMPLE 2 Preparation of (20S)-3-keto-20-hydroxy-18-oic lactone20)allopregnane A solution of l g. of dihydroparavallarine in 15 cc. ofmethylene chloride is mixed with a solution of 650 mg. ofN-chlorosuccinimide in 15 cc. of methylene chloride. The mixture isstirred for 15 minutes at a temperature in the region of 0 C. Afterstanding for l hour at ordinary temperature, the reaction solution iswashed three times with 50 cc. of water. It is dried over sodiumsulphate and it is subjected to vacuum distillation at a temperaturebelow 40 C. The white residue of chloramine is then dried for 1 hour atordinary temperature and at 0.01 mm. Hg. It is then heated under refluxfor 15 minutes with 25 cc. of sodium ethanolate solution in ethanol.

The reaction solution containing a precipitate of sodium chloride insuspension is poured into cc. of a 1% sulphuric acid solution. Theprecipitate formed iS extracted with ether and 650 mg. of deaminatedproduct are obtained. After heating for an hour on a water bath, thesulphuric acid mother liquors are extracted afresh with chloroform and asecond quantity of mg. of deaminated product is thus obtained.

The combination of the products thus isolated and placed in benzonicsolution are subjected to chromatography on l2 g. of alumina. Thebenzene extract yields 494 mg. of a white product (giving a yellowprecipitate immediately with aV solution of 2,4-dinitrophenyl hydra-Zine). By recrystallisation from ether, there is obtained a firstquantity of 260 mg. of the ketone corresponding to the above formula,this melting at 178 C. By concentration of the mother liquors, there areobtained 90 mg. of a second quantity, having the same melting point. Therotatory power of this product is []D20=+17i2 (c.=0.23 chloroform).

The infra-red spectrum of this product is shown in FIG.

2 of the accompanying drawings and a lactone band is observed at5.75/11. and a ketone band at 5.9M.

Analysis of this product, for an empirical formula of CzlHaoOs, gives-Calculated: C=76.32%, H=9.15%, O=l4.53%. Found: C=76.15%, H=8.95%,O=l4.59%.

EXAMPLE 3 Calculated: C=75.86%, H=9.70%, O=14.44%. Found: C=75.54%,H=9.65%, O=14.52%.

EXAMPLE 4 Preparation of (2 0S -3- -acetoxy -2 0-hy droxy-l 8-oc lactone20 -allopregnane O o CH The alcohol obtained in Example 3 is acetylatedwith acetic anhydride and the monoacetylated derivative corresponding tothe above formula is obtained.

For this purpose, 150 mg. of alcohol are heated for 2 hours at 100 C.with 3 cc. of acetic anhydride. The excess of reagent is distilled offin vacuo and the residue is crystallised from a mixture of acetone andhexane. There are thus obtained 130 mg. of the acetylated derivativecorresponding to the above formula. Its melting point is 198 C.

Its rotatory power is [a]D20=-lli2 (c.=0.69 chloroform).

Its intra-red spectrum is shown in FIG. 4 of the accompanying drawings,and a lactone band can be seen at 5.72,:1. and an ester band at 5.82lr.

Analysis of the product, for an empirical formula of C23H3404, gil/5S-Calculated: C=73.76%, H=9.15%, O=17.09%. Found: C=73.75%, H=8.95%,O=17.09%.

I claim:

1. In a process of producing 3-keto steroid compounds of the formulawherein X is a member selected from the group consisting of methyleneand carbonyl;

R1 is a member selected from the group consisting of hydrogen, methyl,and acetyl;

R2 is a member selected -from the group consisting of hydroxyl, acetoxy,and, together with R1, forming a direct oxygen to canbon bond, tocomplete a tive-membered ring; and

Y and Z1 are members selected trom the group consisting of hydrogen anda direct carbon to carbon bond,

the steps which comprise chlorinating the steroid com- 5 pound of theformula OR; Rg CHs N n.0 if

wherein X, R1 and R2 represent the same members as indicated above,while Y and Z are members selected from the group consisting of hydrogenand a direct carbon to carbon bond, to form the 3-(N-chloro-N-methylamino) compound and treating said 3-(N-chloro-N-methyl amino) compoundwith a solution of an alkali metal alcoholate in an anhydrous alcohol toconvert the chloro methylamino group into the keto group.

2. In a process of producing (S)-3-keto-20-hydroxy 18-oic lactone(- 20)-pregna-4-ene, the steps which comprise chlorinating the steroidcompound of the formula o\ 0 on,

CH; O

o- CH; `H

N H3C with N-chloro succinimide in an anhydrous organic solvent to formthe 3-(N-chloro-N-methyl amino) compound and treating said3-(N-chloro-N-methyl amino) compound with a solution of an `alkali metalalcoholate in an anhydrous alcohol to convert the chloro methylaminogroup into the keto group.

treating said 3-(N-chloro-N-methyl amino) compoundv 7 5. In a process ofproducing (2OS)-3 keto20hydroxy 18-oic lactone(- 20)allopregnane, thesteps which comprise chlorinating the steroid compound of the formula toform the 3-(N-chloro-N-methyl amino) compound and treating said3-(N-chloro-N-methyl amino) compound With a solution of `an alkali metalalcoholate in an anhydrous alcohol to convert the chloro methylaminogroup into the keto group.

6. In ya process of producing (208)-3-keto-20-hydroxy- 18oic 1actone(-20)-allopregnane, the steps which comprise treating the steroid compoundof the formula Ha H (- 20)al1opregnane with a solution of an yalkalimetalV borohydn'de in methanol.

8. In a process of producing (20S)-3acetoxy20- hydroxy-l-oic lactone(r20p)-allopregnane, the step which comprises reacting(20S)-3-keto-20-hydroXy-lS-oic lactone(- 20)-allopregnane With asolution of an alkali metal -borohydride in methanol, and acetylatingthe resulting 3,20-dihydroxy compound.

References Cited UNITED STATES PATENTS 3,161,636 12/1964 Le Men26m-239.57

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, M. LIEBMAN, ELBERT L. ROBERTS, Examiners.

H. A. FRENCH, Assistant Examiner.

2. IN A PROCESS OF PRODUCING (20S) 3-KETO-20-HYDROXY18-OIC LACTONE(-->20)-PREGNA-4-ENE, THE STEPS WHICH COMPRISE CHLORINATING THE STEROIDCOMPOUND OF THE FORMULA